A simple route to the indolizidine alkaloid skeleton

Tetrahedron Letters, Vol. 35, No. 49. pp. 9157-9158, 1994 Ekevia Science Ltd Printed in Gnat Britain oo40-4039i94 $7.oota.rJo

0040-4039(94)02060-4

A Simple Route to the Indolizidine Alkaloid Skeleton. Derek Ii. R. Barton,* Maria M. M. AraGjo Pereira and Dennis K. Taylor. wnt

of Chemistry, Texas A&M University, College Station TX 77843-3255,

USA.

Abstract: The Barton-Ester (PTOC) methodology allows for the high yielding synthesis of the indolizidine alkaloid skeleton I2 starting from readily ava&ble (pyrrol-I -yl)acetic acid 7.

The indolizidine alkaloids constitute a family of compounds based on the parent structure 1.1 These compounds

which arc often toxic, are commonly

isolated from the extracts of amphibian skins in minute

quantities and exhibit high biological activity.* The isolation and enantioselective indolizidine alkaloids 2-6 have recently been reported. 2bZG4

syntheses of several key

We report here a simple and high yielding

synthesis of the indolizidine alkaloid skeleton 12. &

@&

&

; Ii

:v (1)

(3)

(2)

(4) R = (CH&-CH, (5) R = (CH&-CH=CH2 (6) R = (CH~&!S CH

Thus, treatment of pyrrol-l-y1 acetic acids with DCC and N-hydroxypyridine-2-thione man&

in the usual

afforded the Barton (FlDCJ ester 87 in nearly quantitative yield as depicted in Scheme 1. Photolysis

of 8 in the presence of excess ethyl acrylate yielded, after workup and subsequent basic hydrolysis, the acid 97 in good yield. Polyphosphoric acid cyclization to lo7 followed by reduction employing zinc / acetic acid gave 6,7-dihydro-8(5H)-indolizinone* reduce

11 in excellent yield. Catalytic hydrogenation with Pd / C failed to

11;however hydrogenation over a Rh /

Alfl3

catalyst9 afforded the desired indolizidine alkaloid 12

in quantitative yield In summary, the Barton-Ester methodology allows for a high yielding synthesis of the indolizidine alkaloid skeleton 12 starting from the readily available acid 7. Also, preliminary experiments show that the same principle is applicable to the synthesis of substituted inclolizidine alkaloids as well as those derived from indole.

9157

9158

0/ \ N

(4 -

(12, 100%)

(10, 89%)

(11,90%)

(a) N-hydroxypyridine-2-thione. DCC, CH&,

25°C; (b) i) ethyl acrylate (10 equiv.),

CH&l,. hv; ii) 20% aq. KOH / MeOH; (c) excess PPA, 16 hr., r.t.; (d) Zn / AcOH, 2.5 hr., r.t.; (e) H,, 65 psi, 5% Rb / Al&, 12 hr. r.t.

Scheme Acknowledgements: References 1.

1

We thank the Welsh foundation for the support of this research.

and Notes:

Takahata, H.; Momose, Takefumi. In The Alkuloids, Cordell, G. A., Ed.; Academic Press: New

York, 1993; Vol. 44, 189-250. 2.

(a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;

Pelletier, S. W.,

Ed.: Wiley: New York, 1986: Vol. 4. l-102; (b) Polniaszck, R. P.; Belmont, S. E. J. Org. Chem.. 1991,56. 4868-4874;

(c) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.;

Lidert, 2.; Swithenbank, C. J. Org. Chem., 1991,56,1393- 1405 and rcfennces cited therein. 3.

Jeffoni, C. W.; Tang, Q.: Zaslona, A. .I. Org. Chem., 1991,113. 3513-3518; Polniaszek. R. P.;

Belmont, S. E. J. Org. Chem., 1990.55.4688-4693; Momose T.; Toyooka, N. J. Org. Chem., 4.

1994,59. 943-94s. Ohmiya. S.: Kubo, H.: Otomasu. H.; Saito, K_: Murakoshi, I. Heterocycles,

5.

Jefford, C. W.; Johncock. W. Helv. Chim. Acta., 1983.66,

6.

Barton, D. H. R; Ozbalik. N.; Vacher, B. Tetrahedron.

7.

All new compounds gave satisfactory spectral and analytical analysis. 9, m.p. (hexanes) 72-730<3,

8.

10, m.p. (CH2C12) 107-108°C. Clemo, G. R.; Ramage. G. R. J. Chem. Sot., 1931. 49-55. Bates, H. A.; Rapoport, H. J. Am. Chem. Sot., 1979.101. 1259-1265.

9.

(Received in USA 7 September

19!W,30, 537-542.

2666-2671.

1988.44,7385-7392.

1994, revised 4 October 1994; accepted 11 October 1994)